Management of Pulmonary Metastases in Osteogenic Sarcoma.

Twenty-three patients presented with isolated pulmonary metastases from osteogenic sarcoma following primary treatment by amputation or limb salvage, combined with chemotherapy. The metastases were treated by conservative surgical excision, combined with chemotherapy; surgicl excision was repeated for recurrent pulmonary metastases provided there were none elsewhere. Six patients are alive and disease free following their initial surgery. Of the remaining 17, 10 had recurrence confined to the lungs, and seven developed extra pulmonary metastases. The ten with isolated pulmonary metastases all had further thoracotomies but eventually seven died, as did all those with extra pulmonary metastases. There were in all 45 operations, with one hospital death and one serious complication. Actuarial survival at 1,3,5 and 7 years was 87, 45, 39 and 31% respectively. In the ten patients who had recurrence of isolated pulmonary metastases, survival at 1 and 3 years was 70 and 34%.


INTRODUCTION
Osteogenic sarcoma is a potentially lethal tumour, haematogenous spread carries the tumour first to the lung, and then elsewhere.In the pre-chemotherapy era treatment was by amputation and irradiation, but never- theless 80% of patients had developed pulmonary secondaries within approximately two years (1-3).Un- treated, 88% of these were dead two years later, and all by five years (2-4).Surgical excision of multiple, and if necessary, recurrent pulmonary metastases led to im- proved results with 28% surviving 5 years (5).The addi- tion of chemotherapy to the surgical treatment was found to further improve survival (6), and since 1974 has been adopted by many centres as the treatment of choice for these patients (3,4,7-14).Since 1976 patients at this centre with pulmonary metastases have been treated with combined chemotherapy and surgical excision.The purpose of this paper is to report the results of this combined treatment with follow-up extending to a max- imum of ten years.

PATIENTS AND METHODS
Between 1976 and 1985 twenty-three patients prospec- tively entered this programme.There were 16 males an, 7 females, aged between 8 and 27 years with a mean ? 15.6 years.Amputation had been performed in 16 P3 tients.Seven patients had had limb conservation us|r1metal endoprostheses.All but one of the twenty-th^, patients had no evidence of pulmonary disease at ini*'3 presentation, and had received adjuvant chemotherapy as part of the primary treatment of the tumour; development of lung metastases therefore indicated failure of the adjuvant chemotherapy programme.
remaining patient already had pulmonary metastas6' when his primary tumour was diagnosed.
On diagnosis of pulmonary metastases, the pat\e?J were fully investigated to exclude metastases eisewher^ including either tomography or a CT scan of the cheS and liver and bone scans.

Chemotherapy
All patients received chemotherapy, the details of wh'c, were dictated by the previous failed programme of a? juvant chemotherapy.The most commonly used Pf0 tocol was; Vincristine 1.5mg/m2 intravenously half 5 hour before an infusion of Methotrexate followed ^ folinic acid rescue.These drugs were given weekly four weeks escalating the Methotrexate dose by 1 9^, each week, to reach 4g/m2.The patient was then assessed and surgery carried out 10 to 14 days from t"1 last course of chemotherapy.Chemotherapy was [e started two weeks after surgery, the regimen being 1,1 fluenced by whether a favourable or unfavourable sponse to the pre-operative chemotherapy had occurre as assessed by the degree of histological damage to ^ tumour.Doxorubicin was added to high-dose Method, xate if the response was favourable, and other dru9 including Actinomycin D, Bleomycin, Cyclophosp^ mide, cis-Platinum and Ifosfamide were used if the {e sponse was unfavourable.

Sur9erY
.* Pulmonary metastases were usually multiple and in vie ^ of the possibility of further recurrence the princip'e conserving lung tissue, with excision of the smalleS possible amount with the tumour, was considered pa1"^ mount (3-5,13).Small lesions tended to be periphe^ and larger lesions were found deeper in the lungs; ther^ fore simple enuncleation was the preferred procedure ^ small lesions, while larger ones needed to be remoVe by more formal resections.For recurrence of metastas^ confined to the lung, further excision was perform^ ' either alone or combined with further chemotherapy 3 appropriate., Forty-five operations were performed, 29 for surgi^ removal of the initial metastases in twenty-three patier1 (six staged bilateral thoracotomies (13), and 16 for rec^ rent metastases (Table 1).In this series median sterP0^ tomy for bilateral metastases was not used (8,15).VVed9 Number of operations performed for initial or recurrent isolated pulmonary metastases showing the incidence of death or major complication.
^section was performed in two patients, segmental re- action in three and lobectomy in one.Three patients ad extension of their recurrent tumour to the chest wall r ^'aphragm, and in each of these the widest possible ^section was undertaken; in all others, the metastases ere removed by local excision. P?"?w-up VerY patient was seen regularly in the outpatient clinic, j*arr|ined for local recurrence or distant spread and Vestigated with at least a plain radiograph and/or a CT l^an-While these patients are being followed indefinite- ' this review was concluded on 31 December 1985.
^istical Methods (lCR\Uar'a' survival was calculated using the Kaplan Meier ' method as described by Anderson et al (17).

RESULTS
in pjr0Su'ts ?f the combined treatment are summarised ancj ^.Ure ^ a" patients survived the initial operations reCurSl* r?main alive and disease-free.Metastases have Pulrr/00' 'n ^ patients, in 7 of whom there was extra- Ten ?narV spread; all seven of these patients are dead.
PuimPat'0nts *1ac' one or rnore recurrence of isolated er Q ?nary metastases and underwent a total of 16 furth- deatherati0ns-'n this group, there was one operative Whii anc' ?subsequent deaths from tumour progression ^ont 3 remain alive, 2 free of disease at 24 and 43 ancj from the time of the first metastatic recurrence thre ?neW'^ a further recurrence at 16 months.The ^eta Patients with chest wall extension of recurrent stases have all died.
6o ^ there are 9 patients alive (range 13-126; median rePort?nt^S wh?m one has disease at the time of rnonth'n^' Fourteen are dead (range 6-69; median 23 Act .a"?f whom had progression of disease.
Vearsu.aria' survival for the whole group at 1, 3, 5 and 7 thoSe 'SJ^' ^9 and 31 % respectively (Figure 2).For enCe ^ 0 had one or more further operations for recurr- ent^ ls?lated pulmonary metastases, survival at 1, 2 Patient8ars 'S anc' ^4% respectively.Eight of the 23 diSeg s achieved a period of one year or more free of had "h e.a^epthe initial surgery, as did four of the 10 who ad further operations.
The o !Ve Mortality and Complications ofSevn'V serious non-fatal complication was an episode first n9re methotrexate toxicity.This arose following the Wh0 L0st"?Perative course of chemotherapy in a patient reserva^ a small residual pleural effusion; this acted as a enter ?lr or third space' from which methotrexate re- ed the systemic circulation after the usual course of folinic acid rescue had been discontinued, resulting in prolonged exposure of susceptible tissues such as bone marrow, gut and mucous membranes to toxic levels of methotrexate.

Surgical Pathology
One hundred and forty-five nodules were removed at the 45 operations with a mean of 3.4 (range 1-18).In all the patients a combination of viable and non-viable tumour cells was identified on histological examination.

Possible Factors in Influencing Survival
The interval between the presentation of the primary tumour and the metastases was considered: of 11 patients free of disease for less than one year, 3 were alive 11 to 110 months following excision of metastases.Among the 11 patients free of disease for more than one year, six are alive 11-109 months later.Examination of age and survival showed that seven of 13 children older than 15 years are alive but only two of 10 under that age.  Figure 2 Actuarial survival curve of the 23 patients (number in brackets is the number of patients entering each six-month period).
However, these differences were not statistically significant, as was also the case for the other two pre- operative or operative factors examined.However, a tumour-free interval of greater than 24 months after the excision of pulmonary metastases doesMndicate an im- proved prospect for survival.Seventeen patients were free of recurrence of disease for periods under 24 months and only 4 of them (23%) are alive at 30,23,11 and 11 months since operation; of 6 patients who were free of recurrence of metastases for over 24 months, 5 (83%) are alive at 9, 9, 6, 6, and 3 years since the operation while one patient died after 25 months (P<0.05).No other factors examined whether pre- operative, operative or post-operative had a significant influence on outcome in this small series.

DISCUSSION
The development of pulmonary metastases following limb amputation for osteogenic sarcoma was universally fatal in the past (2,13,19).Two changes have taken place in the primary treatment of the disease in recent years.First the introduction of chemotherapy in the early 1970s (7,20,21) and, more recently, the development of techni- ques of limb conservation (22,23).The use of effective chemotherapy has modified the behaviour of the tumour so that approximately 50% of patients achieve extended disease-free survival (21,24) and the frequency of occurr- ence of metastases within the first two years is greatly reduced (24).In a proportion of patients the development of metastases appears to be delayed, resulting in a longer tumour-free interval between the presentation of the primary and the appearance of metastases (21).Disease-free survival for two years after the primary treatment can no longer, therefore, be regarded as cure (21); dormant tumours may re-emerge after a longer interval (21), as happened in four of the 23 patients in this report.Limb conservation has greatly enhanced the im- mediate quality of life for those with successful prostheses but it has not yet been fully established whether the chances of local or distant recurrence are different than following amputation (25,26).The treatment of pulmonary secondaries by che- motherapy alone does little to influence the high mortal- ity.Gundry (11) showed that 12 out of 13 patients with pulmonary secondaries treated this way had died after an average of seven months; Schaller (13) found that none survived without surgery.Han (3) reported that 80% of those with pulmonary metastases were dead within 18 months if they were not surgically resected.
Surgery alone, as treatment for pulmonary secondar- ies has met with more success.After Torek (1930) (27), and Barney and Churchill (1939) (28) first excised pulmonary metastases in malignant disease, Sweetnam and Ross (29) reported that eight of 12 patients operated for solitary pulmonary metastases from bone tumours, had survived an average of 6.5 years.This led to an era of excision of the solitary secondary only, usually after some delay to confirm that no other metastasis was present (13,29).The use of surgery alone progressed so that conservative and, if necessary, repeated excision of multiple metastases was undertaken (3,5,9), and five- year survivals of just under 30% were achieved by this method.
By the mid 1970's the use of chemotherapy in the primary treatment of osteogenic sarcoma and a more aggressive surgical approach to pulmonary metastases were both sufficiently established in cancer centres to lead to the development of a multi-disciplinary approach to the management of pulmonary metastases usin9 surgery, chemotherapy and, if needed, radiation (7,10,30).This yielded initially encouraging results with 65% survival at 18 months (10), 58% survival at three years (4) and similar early results from other workers (9)-Longer follow-up, however, has shown that the 4-5 year survival is in the region of 40% in most studies (3,14); slightly higher figures have been reported by some work' ers (11,12), while a recent multi-centre European study found three year survival to be 20% (31).The philosophy of this multidisciplinary approach may be summarised as follows: 1. Osteogenic sarcoma is a systemic disease, whid1 needs systemic treatment as well as local treatment (4).
2. The bulk of the gross disease may be surgically excised, while microscopic disease may be control 'led by chemotherapy (24); adjuvant 'coned-dovvn irradiation may help to control local disease (8,24)- In practice this approach is applicable in patients witf pulmonary metastases if the following criteria are met (5,24).
a) Control of primary disease.b) No extrapulmonary metastases.c) Pulmonary metastases are resectable.d) The patient will tolerate the operation.
Our own experience over a ten-year period has involved the management of 23 patients by these principles.Suf' vival at 5 and 7 years after the presentation of pulmonary metastases was 39% and 31% respectively.Six of the nine survivors have remained free of further recurrence and are living full and independent lives.
It has been claimed that various pre-and intra' operative factors will influence outcome, but there is no general agreement about this.However, post-operative events may also influence survival; in particular, recurf ence of metastases would seem likely to have an adverse effect, though this has not been formally described ?rassessed in the literature.Excision of recurrent metaS' tases by repeat thoracotomy is nevertheless widely advocated (3,5,8,13).
In this series recurrence of tumour appears to affect survival adversely.Those who recurred with extrapu'' monary metastases all died.Of the ten patients who underwent repeat thoractomy for apparently isolated recurrent pulmonary metastases, three are alive but only two free of disease.Three year survival fell from 45% f?r the whole group after the first thoracotomy to 34% f?r this group following repeat thoracotomy.
In the past, two years of disease-free survival after the primary treatment was equated with cure (5); this ,s clearly no longer the case.However, two year disease' free survival after excision of metastases in this serie5 correlated positively with prolonged survival and the risk of further recurrence would seem to be minimal.
For the majority of patients who died, an improved quality of life might still justify the rigours of combined treatment despite ultimate failure.Eight of the 23 pa' tients achieved at least one year of freedom from diseas?
after their first operation and four out of 10 did so after repeat thoracotomy.Although late survival after repeaj thoracotomy appears to be reduced, the prospects achieving one year of freedom from disease are stilj substantial.Therefore, repeat thoracotomy would appear to be justified in those circumstances.
Figure 1 Results of combined treatment.
Figure 1 Results of combined treatment.OSTEOGENIC SARCOMA COMBINED TREATMENT OF PULMONARY METASTASES 1976-1985

Table 1
Mortality and morbidity complicating surgery